Harold C. Simmons Cancer Center High Throughput Screening Shared Resource (Translational Research Resource) Project Summary/Abstract The High Throughput Screening Shared Resource has a strong track record in both chemical and RNAi screening. The former is carried out via full-file and subset screening of our compound library (+230,000 compounds) and by supporting confirmation, dose-response studies, and secondary activity profiling of selected hit compounds as well as synthesized and purchased synthetic analogs. For early, preclinical drug discovery efforts, the Resource provides advanced project support that encompasses structure-activity relationship (SAR) studies, bioassay-guided fractionation of natural products, cheminformatics and bioinformatics support, and data storage and integration via our Laboratory Information Management System (LIMS). For the identification of novel therapeutic protein targets and pathways, the Core carries out screening of genome-wide siRNA libraries and supports confirmation and characterization of the genes and pathways identified as potential points of therapeutic intervention. All of these activities are engaged in ~3900 square feet of laboratory space using the latest in screening technologies and instrumentation by a director who has several years experience in industrial and academic drug discovery and a well trained and experienced scientific staff. Together, the director and scientific staff bring more than 30 years of experience to bear on every screening project. The Resource works collaboratively with principal investigators (biologists, chemists, and statisticians) and other shared resource and core facilities to achieve both therapeutic and basic research goals. The success and impact of the Resource can also be measured in terms of the pre-clinical drug and target discovery activities that are enabled downstream of screening. To date, the Resource has executed over 195 screening projects (98 small molecule and 97 RNAi screens). From these efforts, over 64 publications derived from high throughput screening have appeared in high profile journals and the patent literature. These results have provided the foundation for successful funding of over 60 grant applications for screening programs and advanced characterization of established chemical leads and drug targets. Importantly, several discoveries from screening programs have led to commercial follow up via licensing. One of the keys to our success as a collaborative core facility has been the tight integration of our expertise with medicinal chemistry, ADME (Absorption, Distribution, Metabolism, and Excretion), and in vivo efficacy. Seven (7) chemistry faculty members in the Biochemistry Department enable lead optimization and development in pre-clinical drug discovery programs. Their efforts are supported and enhanced by the Pharmacology Core which carries out ADME, toxicity, and efficacy studies. In sum, the multidiscipline and collaborative environment of pre-clinical drug and target discovery is effectively and productively integrated with cutting edge research in cancer biology by Simmons Cancer Center members.